Mucoadhesive, syringeable drug delivery systems for controlled application of metronidazole to the periodontal pocket: In vitro release kinetics, syringeability, mechanical and mucoadhesive properties

Novel mucoadhesive formulations containing hydroxyethylcellulose (HEC; 3 and 5%, w/w) or Carbopol (3 and 5%, w/w), polycarbophil (PC; 1 and 3%, w/w) and metronidazole (5%, w/w) at pH 6.8 were designed for the treatment of periodontal diseases. Each formulation was characterised in terms of hardness, compressibility, adhesiveness and cohesiveness (using Texture Profile Analysis), drug release, adhesion to a mucin disc (measured as a detachment force using the texture analyser in tensile mode) and, finally, syringeability (using the texture analyser in compression mode). Drug release from all formulations was non-diffusion controlled. Drug release was significantly decreased as the concentration of each polymeric component was increased, due to both the concomitant increased viscosity of the formulations and, additionally, the swelling kinetics of PC following contact with dissolution fluid. Increasing the concentrations of each polymeric component significantly increased formulation hardness, compressibility, adhesiveness, mucoadhesion and syringeability, yet decreased cohesiveness. Increased product hardness, compressibility and syringeability were due to polymeric effects on formulation viscosity. The effects on cohesiveness may be explained both by increased viscosity and also by the increasing semi-solid nature of products containing 5% HEC or Carbopol and PC (1 or 3%). The observations concerning formulation adhesiveness/mucoadhesion illustrate the adhesive nature of each polymeric component. Greatest adhesion was noted in formulations where neutralisation of PC was maximally suppressed. For the most part, increased time of contact between formulation and mucin significantly increased the required force of detachment, due to the greater extent of mucin polymer hydration and interpenetration with the formulations. Significant statistical interactions were observed between the effects of each polymer on drug release and mechanical/mucoadhesive properties. These interactions may be explained by formulatory effects on the extent of swelling of PC. In conclusion, the formulations described offered a wide range of mechanical and drug release characteristics. Formulations containing HEC exhibited superior physical characteristics for improved drug delivery to the periodontal pocket and are now the subject of long-term clinical investigations. (C) 1997 Elsevier Science B.V.

Influence of a pore-forming agent on swelling, network parameters, and permeability of poly(ethylene glycol)-crosslinked poly(methyl vinyl ether-co-maleic acid) hydrogels:Application in transdermal delivery systems

We characterized hydrogels, prepared from aqueous blends of poly(methyl vinyl ether-co-maleic acid) (PMVE/MA) and poly(ethylene glycol) (PEG 10,000 Daltons) containing a pore-forming agent (sodium bicarbonate, NaHCO ). Increase in NaHCO content increased the equilibrium water content (EWC) and average molecular weight between crosslinks (M ) of hydrogels. For example, the %EWC was 731, 860, 1109, and 7536% and the M was 8.26, 31.64, 30.04, and 3010.00 × 10 g/mol for hydrogels prepared from aqueous blends containing 0, 1, 2, and 5% w/w of NaHCO , respectively. Increase in NaHCO content also resulted in increased permeation of insulin. After 24 h, percentage permeation was 0.94, 3.68, and 25.71% across hydrogel membranes prepared from aqueous blends containing 0, 2, and 5% w/w of NaHCO , respectively. Hydrogels containing the pore-forming agent were fabricated into microneedles (MNs) for transdermal drug delivery applications by integrating the MNs with insulin-loaded patches. It was observed that the mean amount of insulin permeating across neonatal porcine skin in vitro was 20.62% and 52.48% from hydrogel MNs prepared from aqueous blends containing 0 and 5% w/w of NaHCO . We believe that these pore-forming hydrogels are likely to prove extremely useful for applications in transdermal drug delivery of biomolecules. © 2012 Wiley Periodicals, Inc.

Physical characterisation and component release of poly(vinyl alcohol)-tetrahydroxyborate hydrogels and their applicability as potential topical drug delivery systems

Poly(vinyl alcohol)-tetrahydroxyborate (PVA-THB) hydrogels are dilatant formulations with potential for topical wound management. To support this contention, the physical properties, rheological behaviour and component release of candidate formulations were investigated. Oscillatory rheometry and texture profile analysis were used at room temperature and 37 °C. Results showed that it was possible to control the rheological and textural properties by altering component concentration and modifying the type of PVA polymer used. Hydrogels made using PVA grades with higher degrees of hydrolysis displayed favourable characteristics from a wound healing perspective. In vitro release of borate and PVA were assessed in order to evaluate potential clinical dosing of free species originating from the hydrogel structure. Component diffusion was influenced by both concentration and molecular weight, where relevant, with up to 5% free PVA cumulative release observed after 30 min. The results of this study demonstrated the importance of poly(vinyl alcohol) selection for ensuring appropriate gel formation in PVA-THB hydrogels. The benefits of higher degrees of hydrolysis, in particular, included lower excipient release and reduced bioadhesion. The unique physical characteristics of these hydrogels make them an appealing delivery vehicle for chronic and acute wound management purposes.

Development and characterization of self-assembling nanoparticles using a bio-inspired amphipathic peptide for gene delivery

The design of a non-viral gene delivery vehicle capable of delivering and releasing a functional nucleic acid cargo intracellularly remains a formidable challenge. For systemic gene therapy to be successful a delivery vehicle is required that protects the nucleic acid cargo from enzymatic degradation, extravasates from the vasculature, traverses the cell membrane, disrupts the endosomal vesicles and unloads the cargo at its destination site, namely the nucleus for the purposes of gene delivery. This manuscript reports the extensive investigation of a novel amphipathic peptide composed of repeating RALA units capable of overcoming the biological barriers to gene delivery both in vitro and in vivo. Our data demonstrates the spontaneous self-assembly of cationic DNA-loaded nanoparticles when the peptide is complexed with pDNA. Nanoparticles were < 100 nm, were stable in the presence of serum and were fusogenic in nature, with increased peptide α-helicity at a lower pH. Nanoparticles proved to be non-cytotoxic, readily traversed the plasma membrane of both cancer and fibroblast cell lines and elicited reporter-gene expression following intravenous delivery in vivo. The results of this study indicate that RALA presents an exciting delivery platform for the systemic delivery of nucleic acid therapeutics.

Towards Organic Electronic Materials for Electrically Stimulated Gene Delivery

The cell-specific delivery of polynucleic acids (e.g., DNA, RNA), gene therapy, has the potential to treat various diseases. In this chapter we discuss the use of organic electronic materials as non-viral gene delivery vectors and the great potential for electrochemically triggered gene delivery. We highlight some examples in this chapter based on fullerenes (bucky balls and carbon nanotubes), graphenes and electroactive polymers, particularly those that include experiments in vivo.